Alcohol drinking and cigarette smoking are highly correlated with a greater preponderance of heavy smokers among alcoholics than among the general population suggesting a common mechanism in the conjoint abuse of both alcohol and cigarettes (nicotine). The purpose of this study is to establish a role for the endogenous opioid in nicotine and alcohol dependence by evaluating the ability of the opioid antagonist naloxone, to precipitate withdrawl symptons, similar to those seen in opiate withdrawal, in male and female, alcohol and nicotine dependent individuals and normal subjects. Subjects will be challenged with two separate doses of naloxone or placebo and observed for signs and symptoms of opiate withdrawl, as well as changes in craving for alcohol and nicotine. The specific aims of this proposal are: 1) to determine whether the opioid antagonist naloxone precipitates a withdrawl syndrome in nicotine dependent individuals; 2) to determne whether naloxone precipitates a withdrawl syndrome in alcoholics; 3) to determine if the naloxone- precipitated withdrawl syndrome is different for men and women; 4) to evaluate the severity of withdrawl in individuals who are co-dependent on alcohol and nicotine; and 5) to model neuroendocrine changes during naloxone-precipitated withdrawl. To date 14 smokers and nonsmokers have participated in the study. Smokers experienced greater dose-related increases in total CINA scores, specifically in withdrawl symptoms such as nevousness, restlessness, muscle tension, feeling hot/cold, gooseflesh, sweating and nasal congestion compared with nonsmokers. The contribution of alcohol dependence to opiate withdrawl symptoms was also tested in alcohol dependent subjects (>25 drinks/week) who were smokers/nonsmokers but we have not yet analysed these data. We plan to continue recruiting alcohol and nicotine, dependent and non-dependent subjects.